A Machine Learning Approach Enables Quantitative Measurement of Liver Histology and Disease Monitoring in NASH.

BACKGROUND AND AIMS: Manual histological assessment is currently the accepted standard for diagnosing and monitoring disease progression in NASH, but is limited by variability in interpretation and insensitivity to change. Thus, there is a critical need for improved tools to assess liver pathology in order to risk stratify NASH patients and monitor treatment response. APPROACH AND RESULTS: Here, we describe a machine learning (ML)-based approach to liver histology assessment, which accurately characterizes disease severity and heterogeneity, and sensitively quantifies treatment response in NASH. We use samples from three randomized controlled trials to build and then validate deep convolutional neural networks to measure key histological features in NASH, including steatosis, inflammation, hepatocellular ballooning, and fibrosis. The ML-based predictions showed strong correlations with expert pathologists and were prognostic of progression to cirrhosis and liver-related clinical events. We developed a heterogeneity-sensitive metric of fibrosis response, the Deep Learning Treatment Assessment Liver Fibrosis score, which measured antifibrotic treatment effects that went undetected by manual pathological staging and was concordant with histological disease progression. CONCLUSIONS: Our ML method has shown reproducibility and sensitivity and was prognostic for disease progression, demonstrating the power of ML to advance our understanding of disease heterogeneity in NASH, risk stratify affected patients, and facilitate the development of therapies.

Routine diagnostic arthroscopy with elbow ulnar collateral ligament reconstruction does not reduce the need for future valgus extension overload-related surgeries: a systematic review and meta-analysis.

BACKGROUND: Valgus extension overload syndrome (VEOS) most commonly affects overhead athletes and consists of a constellation of conditions involving the medial, posterior, and lateral elbow, with the most widely discussed being ulnar collateral ligament (UCL) injuries. Many athletes with UCL tears also have findings consistent with other VEOS conditions, though these are not consistently symptomatic. Given the high rate of concomitant pathology, many authors have recommended performing arthroscopy at the time of UCL reconstruction (UCLR) to diagnose and address concomitant VEOS pathology; however, it is not known if this practice actually leads to a reduction in subsequent surgeries for VEOS conditions following index UCLR. The purpose of this systematic review and meta-analysis was to determine if performing routine diagnostic arthroscopy (RDA) in patients undergoing UCLR was associated with a lower incidence of future VEOS-related surgery. METHODS: This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with the primary outcome of interest being the likelihood of needing future surgery to address VEOS conditions with or without RDA at the time of index UCLR. The proportion and incidence rate of subsequent VEOS-related surgeries following UCLR with and without RDA were compared in mixed effects models. RESULTS: There were 25 eligible studies from an initial 1335 systematically identified articles, with results for 2118 UCLR cases. Among these, there were a total of 94 reported VEOS-related surgeries. The proportion of subsequent VEOS-related surgeries was lower when UCLR was performed with RDA (0.40%, 95% CI 0.00%-3.51%) than without (1.16%, 95% CI 0.03%-3.25%), but the difference was not significant (P = .584). The incidence rate of VEOS-related surgeries was 0.16 (95% CI 0.00-0.95) per 100 person-years with RDA and 0.14 (95% CI 0.00-0.55) per 100 person-years without RDA (P = .942). CONCLUSION: RDA preceding UCLR does not significantly reduce the proportion or rate of subsequent surgery for other VEOS conditions. There has been a decrease in RDA utilization with UCLR over time for athletes with torn/incompetent UCLs but otherwise no known symptomatic VEOS conditions, and this trend appears to be justified based on these findings.

Further Defining the 2012 Multi-Society Task Force Guidelines for Surveillance of High-risk Adenomas: Is a 3-Year Interval Needed for All Patients?

GOALS: We set out to determine whether variation from this 3-year follow-up interval was associated with the finding of subsequent high-risk adenoma (HRA). BACKGROUND: HRAs include the following: (1) an adenoma measuring ≥10 mm, (2) ≥3 adenomas found during a single procedure, and (3) an adenoma with high-grade dysplasia or villous architecture. The current Multi-Society Task Force guideline for timing of surveillance colonoscopy after removal of a HRA is 3 years. STUDY: In 2016, we analyzed 495 patients who had a HRA removed during a 2008 colonoscopy. We compared the frequency of finding another HRA at follow-up intervals. We used the current guidelines as our referent group and performed logistical regression to identify whether any patient characteristics, procedural factors, or type of HRA predicted the development of HRAs on follow-up colonoscopy. RESULTS: Individuals who followed-up at a median of 4.5 years did not have more HRA on follow-up compared with those who followed-up at 3 years (25.2% vs. 21.0%, P=0.062). These groups had similar baseline characteristics. Older individuals, male gender, having a history of polyps, and piecemeal resection of an HRA predicted future HRAs. The removal of ≥3 adenomas in 2008 as well as a combination of multiple, large, and advanced polyps showed a higher risk of future HRAs. CONCLUSIONS: The 2012 Multi-Society Task Force recommendation of 3-year follow-up after removal of HRAs may not apply to all patients. We showed that a combination of patient demographics, procedural factors, and pathology best determines the surveillance colonoscopy interval.

Microscopic/"Backwash" Ileitis and Its Association With Colonic Disease in New Onset Pediatric Ulcerative Colitis.

BACKGROUND: Microscopic ileitis and its association with pancolitis in adults with ulcerative colitis (UC) have been described. The incidence of ileitis and associations with colonic disease in pediatric UC have, however, not been thoroughly investigated. This study was undertaken to examine the prevalence of microscopic ileal inflammation at the time of initial diagnosis in a cohort of children with UC. METHODS: We reviewed colonoscopy and biopsy data at time of diagnosis from 105 children and young adults with treatment naïve UC; ileal and colonic mucosal biopsies were available on all patients. Ileal mucosal biopsies were examined for the presence and severity of ileal inflammation, and other histologic features. Concurrently obtained colonic mucosal biopsies were assessed to define the severity, distribution, and extent of disease; endoscopic and clinical follow-up data were reviewed. RESULTS: A total of 107 ileal mucosal biopsies and 693 corresponding colonic mucosal biopsies were examined. Seventeen of 105 patients (16%) were found to have ileal inflammation (mean age = 10.4 years, 59% girls), 14 (82%) of whom had histologic pancolitis. The presence of ileal inflammation was significantly associated with endoscopic pancolitis (P = 0.02). The association between histologic pancolitis, severity of active inflammation in the cecum, and ascending colon suggested a possible association with ileal inflammation (P = 0.06, 0.07, and 0.08 respectively), but did not reach statistical significance. CONCLUSION: Patients with new onset UC may have microscopic ileal inflammation at time of diagnosis, even if the terminal ileum appears macroscopically normal. The presence of endoscopic pancolitis is associated with the presence of histologic ileitis. In contrast to existing studies in adults, an association between the presence of ileitis and the histologic severity or the histologic extent of colitis was not observed. Children with microscopic ileitis in the context of UC do not need to be reclassified as "indeterminate colitis" or Crohn disease.

Pathological Margin Clearance and Survival After Pancreaticoduodenectomy in a US and European Pancreatic Center.

BACKGROUND: The optimal definition of a margin-negative resection and its exact prognostic significance on survival in resected pancreatic adenocarcinoma remains unknown. This study was designed to assess the relationship between pathological margin clearance, margin type, and survival. METHODS: Patients who underwent pancreaticoduodenectomy with curative intent at two academic institutions, in Amsterdam, the Netherlands, and Boston, Massachusetts, between 2000 and 2014 were retrospectively evaluated. Overall survival, recurrence rates, and progression-free survival (PFS) were assessed by Kaplan-Meier estimates and multivariate Cox proportional hazards analysis, according to pathological margin clearance and type of margin involved. RESULTS: Of 531 patients identified, the median PFS was 12.9, 15.4, and 24.1 months, and the median overall survival was 17.4, 22.9, and 27.7 months for margin clearances of 0, < 1, and ≥1 mm, respectively (all log-rank p < 0.001). On multivariate analysis, patients with a margin clearance of ≥1 mm demonstrated a survival advantage relative to those with 0 mm clearance [hazard ratio (HR) 0.71, p < 0.01], whereas survival was comparable for patients with a margin clearance of < 1 mm versus 0 mm (HR: 0.93, p = 0.60). Patients with involvement (0 or < 1 mm margin clearance) of the SMV/PV margin demonstrated prolonged median overall survival (25.7 months) relative to those with SMA involvement (17.5 months). CONCLUSIONS: In patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma, a margin clearance of ≥1 mm correlates with improved survival relative to < 1 mm clearance and may be a more accurate predictor of a complete margin-negative resection in pancreatic cancer. The type of margin involved also appears to impact survival.

Surgical Management of Gallbladder Cancer: Simple Versus Extended Cholecystectomy and the Role of Adjuvant Therapy.

OBJECTIVE: To assess if simple cholecystectomy with adjuvant therapy could provide outcomes comparable to extended cholecystectomy. BACKGROUND: Current guidelines recommend extended/radical cholecystectomy for T2/T3 gallbladder cancer; however, many tumors are discovered incidentally at laparoscopic cholecystectomy. METHODS: The national Cancer Data Base 2004 to 2014 was queried for patients with pT2/T3 gallbladder adenocarcinoma who underwent resection. Adjuvant therapy was defined as chemotherapy, with or without radiotherapy, within 90 days of surgery. Baseline characteristics and overall survival were compared by χ and Kaplan-Meier method, respectively. One-to-one propensity score matching for receipt of adjuvant therapy was used to account for potential selection bias. RESULTS: A total of 6825 patients were identified. Diagnosis was made predominantly (78.9%) at the time of surgery or on pathology; 31.8% (2168) received adjuvant therapy. The majority, 88.8% (6060), had a simple cholecystectomy. Patients who received adjuvant therapy versus surgery alone were more likely to: be younger, privately insured, have no comorbidities, pT3 disease, positive lymph nodes, positive resection margins, and extended cholecystectomy. After matching, median survival was significantly longer for extended cholecystectomy with adjuvant therapy (23.3 months) than cholecystectomy with adjuvant therapy (16.4 months), which was significantly longer than either simple (12.4 months) or extended (10.7 months) cholecystectomy alone (all log-rank P<0.001). CONCLUSIONS: Adjuvant therapy prolongs survival after resection of T2/T3 tumors. Simple cholecystectomy with adjuvant therapy appears to be superior to extended resection alone in the short term and may serve as a potential alternative to re-resection in select high-risk individuals.

Serum I-FABP Detects Gluten Responsiveness in Adult Celiac Disease Patients on a Short-Term Gluten Challenge.

OBJECTIVES: Response to gluten challenge (GC) is a key feature in diagnostic algorithms and research trials in celiac disease (CD). Currently, autoantibody titers, late responders to GC, and invasive duodenal biopsies are used to evaluate gluten responsiveness. This study investigated the accuracy of serum intestinal-fatty acid binding protein (I-FABP), a marker for intestinal epithelial damage, to predict intestinal damage during GC in patients with CD. METHODS: Twenty adult CD patients in remission underwent a two-week GC with 3 or 7.5 g of gluten daily. Study visits occurred at day -14, 0, 3, 7, 14, and 28. Serum I-FABP, antibodies to tissue transglutaminase (tTG-IgA), deamidated gliadin peptides (IgA-DGP), and anti-actin (AAA-IgA) were assessed at each visit. Villous-height to crypt-depth ratio (Vh:Cd) and intraepithelial lymphocyte (IEL) count were evaluated at day -14, 3, and 14. Forty-three CD-serology negative individuals were included to compare serum I-FABP levels in CD patients on a gluten-free diet (GFD) with those in healthy subjects. RESULTS: Serum I-FABP levels increased significantly during a two-week GC. In contrast, the most pronounced autoantibody increase was found at day 28, when patients had already returned to a GFD for two weeks. IgA-AAA titers were only significantly elevated at day 28. I-FABP levels and IEL count correlated at baseline (r=0.458, P=0.042) and at day 14 (r=0.654, P=0.002) of GC. Neither gluten dose nor time on a GFD influenced I-FABP change during GC. CONCLUSIONS: Serum I-FABP levels increased significantly during a two-week GC in adult CD patients and correlated with IEL count. The data suggest that serum I-FABP is an early marker of gluten-induced enteropathy in celiac patients and may be of use in both clinical and research settings.

Efficiency of cell-free and cell-associated virus in mucosal transmission of human immunodeficiency virus type 1 and simian immunodeficiency virus.

Effective strategies are needed to block mucosal transmission of human immunodeficiency virus type 1 (HIV-1). Here, we address a crucial question in HIV-1 pathogenesis: whether infected donor mononuclear cells or cell-free virus plays the more important role in initiating mucosal infection by HIV-1. This distinction is critical, as effective strategies for blocking cell-free and cell-associated virus transmission may be different. We describe a novel ex vivo model system that utilizes sealed human colonic mucosa explants and demonstrate in both the ex vivo model and in vivo using the rectal challenge model in rhesus monkeys that HIV-1-infected lymphocytes can transmit infection across the mucosa more efficiently than cell-free virus. These findings may have significant implications for our understanding of the pathogenesis of mucosal transmission of HIV-1 and for the development of strategies to prevent HIV-1 transmission.

Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease.

OBJECTIVE: Coeliac disease is defined by gluten responsiveness, yet there are few data on gluten challenge (GC) in adults on a gluten-free diet. Lack of data regarding the kinetics of responses to gluten is a limitation in clinical practice and research when GC is performed. DESIGN: 20 adults with biopsy-proven coeliac disease participated. The study included two run-in visits followed by a 14-day GC at a randomly assigned dose of 3 or 7.5 g of gluten/day. Study visits occurred 3, 7, 14 and 28 days after starting GC. Duodenal biopsy was performed during the run-in and at days 3 and 14 of GC. Villous height to crypt depth ratio (Vh:Cd) and intraepithelial lymphocyte (IEL) count/100 enterocytes were measured by two pathologists. Antibodies to tissue transglutaminase and deamidated gliadin peptides, lactulose to mannitol ratio (LAMA) and symptoms were assessed at each visit. RESULTS: Significant reduction in Vh:Cd (2.2-1.1, p<0.001) and increase in IELs (32.6-51.8, p<0.001) were seen from baseline to day 14. Antibody titres increased slightly from baseline to day 14 of GC but markedly by day 28. LAMA did not change significantly. Gastrointestinal symptoms increased significantly by day 3 and returned to baseline by day 28. No differences were seen between the two gluten doses. CONCLUSIONS: 14 day GC at ≥ 3 g of gluten/day induces histological and serological changes in the majority of adults with coeliac disease. These data permit accurate design of clinical trials and indicate that many individuals will meet coeliac diagnostic criteria after a 2-week GC.

The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice.

BACKGROUND: Clostridium difficile mediates intestinal inflammation by releasing toxin A (TxA), a potent enterotoxin. Cathelicidins (Camp as gene name, LL-37 peptide in humans and mCRAMP peptide in mice) are antibacterial peptides that also posses anti-inflammatory properties. OBJECTIVES: To determine the role of cathelicidins in models of Clostridium difficile infection and TxA-mediated ileal inflammation and cultured human primary monocytes. DESIGN: Wild-type (WT) and mCRAMP-deficient (Camp(-/-)) mice were treated with an antibiotic mixture and infected orally with C difficile. Some mice were intracolonically given mCRAMP daily for 3 days. Ileal loops were also prepared in WT mice and treated with either saline or TxA and incubated for 4 h, while some TxA-treated loops were injected with mCRAMP. RESULTS: Intracolonic mCRAMP administration to C difficile-infected WT mice showed significantly reduced colonic histology damage, apoptosis, tissue myeloperoxidase (MPO) and tumour necrosis factor (TNF)α levels. Ileal mCRAMP treatment also significantly reduced histology damage, tissue apoptosis, MPO and TNFα levels in TxA-exposed ileal loops. WT and Camp(-/-) mice exhibited similar intestinal responses in both models, implying that C difficile/TxA-induced endogenous cathelicidin may be insufficient to modulate C difficile/TxA-mediated intestinal inflammation. Both LL-37 and mCRAMP also significantly reduced TxA-induced TNFα secretion via inhibition of NF-κB phosphorylation. Endogenous cathelicidin failed to control C difficile and/or toxin A-mediated inflammation and even intestinal cathelicidin expression was increased in humans and mice. CONCLUSION: Exogenous cathelicidin modulates C difficile colitis by inhibiting TxA-associated intestinal inflammation. Cathelicidin administration may be a new anti-inflammatory treatment for C difficile toxin-associated disease.

A case report of a prostate cancer metastasis in the pancreas exhibiting vascular encasement.

We report a patient who presented with a 4-month history of intermittent epigastric pain. Computed tomography (CT) angiography of the abdomen demonstrated a stenotic celiac trunk but also encasement of the common proper hepatic artery, gastroduodenal artery, and proper hepatic artery by an ill-defined hypoattenuating mass of the pancreatic head. Biopsy confirmed metastatic prostate cancer to the pancreas that occurred 4 years after radiation and androgen deprivation therapy. A follow-up staging study demonstrated an osseous metastasis at the T4 spinous process. This case demonstrates an unusual case of prostate metastasis to the pancreas with the involvement of a main abdominal vessel. With treatment improvements leading to longer survival rates from prostate cancer, radiologists should be aware of atypical metastases that may arise in the long term.

Increased susceptibility of melanin-concentrating hormone-deficient mice to infection with Salmonella enterica serovar Typhimurium.

Melanin-concentrating hormone (MCH) was initially identified in mammals as a hypothalamic neuropeptide regulating appetite and energy balance. However, the wide distribution of MCH receptors in peripheral tissues suggests additional functions for MCH which remain largely unknown. We have previously reported that mice lacking MCH develop attenuated intestinal inflammation when exposed to Clostridium difficile toxin A. To further characterize the role of MCH in host defense mechanisms against intestinal pathogens, Salmonella enterocolitis (using Salmonella enterica serovar Typhimurium) was induced in MCH-deficient mice and their wild-type littermates. In the absence of MCH, infected mice had increased mortality associated with higher bacterial loads in blood, liver, and spleen. Moreover, the knockout mice developed more-severe intestinal inflammation, based on epithelial damage, immune cell infiltrates, and local and systemic cytokine levels. Paradoxically, these enhanced inflammatory responses in the MCH knockout mice were associated with disproportionally lower levels of macrophages infiltrating the intestine. Hence, we investigated potential direct effects of MCH on monocyte/macrophage functions critical for defense against intestinal pathogens. Using RAW 264.7 mouse monocytic cells, which express endogenous MCH receptor, we found that treatment with MCH enhanced the phagocytic capacity of these cells. Taken together, these findings reveal a previously unappreciated role for MCH in host-bacterial interactions.

Anti-melanin-concentrating hormone treatment attenuates chronic experimental colitis and fibrosis.

Fibrosis represents a major complication of several chronic diseases, including inflammatory bowel disease (IBD). Treatment of IBD remains a clinical challenge despite several recent therapeutic advances. Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide shown to regulate appetite and energy balance. However, accumulating evidence suggests that MCH has additional biological effects, including modulation of inflammation. In the present study, we examined the efficacy of an MCH-blocking antibody in treating established, dextran sodium sulfate-induced experimental colitis. Histological and molecular analysis of mouse tissues revealed that mice receiving anti-MCH had accelerated mucosal restitution and lower colonic expression of several proinflammatory cytokines, as well as fibrogenic genes, including COL1A1. In parallel, they spared collagen deposits seen in the untreated mice, suggesting attenuated fibrosis. These findings raised the possibility of perhaps direct effects of MCH on myofibroblasts. Indeed, in biopsies from patients with IBD, we demonstrate expression of the MCH receptor MCHR1 in α-smooth muscle actin(+) subepithelial cells. CCD-18Co cells, a primary human colonic myofibroblast cell line, were also positive for MCHR1. In these cells, MCH acted as a profibrotic modulator by potentiating the effects of IGF-1 and TGF-ß on proliferation and collagen production. Thus, by virtue of combined anti-inflammatory and anti-fibrotic effects, blocking MCH might represent a compelling approach for treating IBD.

Defining the accuracy of secretin pancreatic function testing in patients with suspected early chronic pancreatitis.

OBJECTIVES: The diagnosis of chronic pancreatitis in patients with characteristic symptoms but normal pancreatic imaging is challenging. Assessment of pancreatic function through secretin pancreatic function testing (SPFT) has been advocated in this setting, but its diagnostic accuracy is not fully known. METHODS: This was a retrospective review of patients who received SPFT at our tertiary care institution between January 1995 and December 2008 for suspected chronic pancreatitis. For all patients, medical records were reviewed for evidence of subsequent development of chronic pancreatitis by imaging and/or pathology. Patients were then categorized as "true positive" or "true negative" for chronic pancreatitis based on follow-up imaging or histologic evidence. RESULTS: In all, 116 patients underwent SPFT. Of the 27 patients who tested positive, 7 were lost to follow-up. Of the remaining 20 SPFT-positive patients, 9 (45%) developed radiologic or histologic evidence of chronic pancreatitis after a median of 4 years (1-11 years). Of the 89 patients who had negative SPFT testing, 19 were lost to follow-up. Of the remaining 70 patients, 2 were eventually diagnosed with chronic pancreatitis based on subsequent imaging/histology after a median follow-up period of 7 years (3-11 years). The sensitivity of the SPFT in diagnosing chronic pancreatitis was 82% with a specificity of 86%. The positive predictive value (PPV) of chronic pancreatitis was 45% with a negative predictive value (NPV) of 97%. CONCLUSIONS: In patients with suspected early chronic pancreatitis and normal pancreatic imaging, SPFT is highly accurate at ruling out early chronic pancreatitis with a NPV of 97%.

Prognostic implications of the magnetic resonance imaging appearance in papillary renal cell carcinoma.

OBJECTIVE: To evaluate the prognostic implications of the MRI appearance and pathological features of papillary renal cell carcinoma (pRCC). METHODS: A total of 128 pRCC in 115 patients who underwent preoperative MRI were characterised in terms of pathological type (type 1 vs. type 2), MRI appearance (focal vs. infiltrative) and additional MRI features. Patients were classified on the basis of the presence or absence of metastatic disease. RESULTS: There were 65 focal type 1, 54 focal type 2 and 9 infiltrative pRCC. All infiltrative pRCC were of histopathological type 2. Renal vein thrombus was present in 89 % of infiltrative pRCC and no cases of focal pRCC. Metastatic disease was observed in 3.7 % of focal type 1, 7.5 % of focal type 2 and 75.0 % of infiltrative type 2 pRCC. Infiltrative MRI appearance was a significant predictor of metastatic disease, independent of pathological type, size and T stage (P ≤ 0.020). Among focal pRCC on MRI, pathological type 2 was not a significant predictor of metastatic disease (P = 0.648). No combination of features achieved significantly greater accuracy for predicting metastatic disease than renal vein thrombus alone (P > 0.5). CONCLUSION: Infiltrative MRI appearance and renal vein thrombus identify a subset of pathological type 2 pRCC at a significantly increased risk of metastatic disease.

The incidence and clinical spectrum of refractory celiac disease in a north american referral center.

OBJECTIVES: Refractory celiac disease (RCD) is one of the most serious causes of persistent symptoms in patients with celiac disease (CD). Published reports suggest that approximately half of patients in Europe are RCD type II, which carries a poor prognosis with a 5-year survival rate of ~50% compared with ~90% for RCD type I. However, disease patterns may be different in North America. The aim of this study was to explore the clinical spectrum of RCD in a North American population. METHODS: Medical records of patients with biopsy-proven CD presenting to our institution were reviewed for a diagnosis of RCD. Demographic data, clinical characteristics, and mortality were evaluated and compared with our general CD population. RESULTS: In all, 34 out of 844 (4.0%) CD patients had RCD. The cumulative incidence of RCD for patients diagnosed with CD at our center was 1.5%. Unintentional weight loss at diagnosis of RCD was found in 76.5% (n=26) compared with 16.7% (n=141) at diagnosis of CD (P<0.0001) and diarrhea at diagnosis of RCD was found in 79.4% (n=27) compared with 40.5% (342) at diagnosis of CD (P<0.0001). Five patients (14.7%) were diagnosed with RCD type II and of these, two died of enteropathy-associated lymphoma within 24 months of diagnosis of CD (observed mortality rate 5.9%). CONCLUSIONS: Although RCD is a serious condition with significant morbidity; the observed mortality rates are low in our population. This study suggests that RCD may be less severe in North American vs. European populations.

Small intestinal release mesalamine for the treatment of refractory celiac disease type I.

GOAL: The goal of this study is to evaluate the safety and efficacy of Small intestinal release mesalamine (SIRM) for symptom relief in refractory celiac disease (RCD). BACKGROUND: Therapeutic options for the RCD are inadequate and treatment with corticosteroids and immunosuppressants is limited by side effects. SIRM has been shown to have local antiinflammatory action and excellent tolerability. STUDY: We reviewed records of the RCD patients who received SIRM in an open-label therapeutic trial. Data included demographics, disease characteristics, dose and duration of SIRM therapy, and response. Response was categorized as complete if there was complete resolution of symptoms, partial if there was at least 50% improvement, and nonresponsive if there was less than 50% improvement. RESULTS: Four patients were treated with SIRM alone and 6 received SIRM and oral budesonide. Within 4 weeks, 50% had complete response and an additional 10% had partial response. Two of the 6 patients were able to discontinue budesonide. One patient discontinued SIRM owing to headaches. CONCLUSION: SIRM seems to be a safe and efficacious treatment option in patients with RCD. Larger, controlled trials of this agent are warranted.

Celiac crisis is a rare but serious complication of celiac disease in adults.

BACKGROUND & AIMS: Celiac crisis is a life-threatening syndrome in which patients with celiac disease have profuse diarrhea and severe metabolic disturbances. Celiac crisis is rare among adults and not well documented. To improve awareness of this condition and to facilitate diagnosis, we reviewed cases of celiac crisis to identify presenting features, formulate diagnostic criteria, and develop treatment strategies. METHODS: Cases of biopsy-proven celiac disease were reviewed. Celiac crisis was defined as acute onset or rapid progression of gastrointestinal symptoms that could be attributed to celiac disease and required hospitalization and/or parenteral nutrition, along with signs or symptoms of dehydration or malnutrition. RESULTS: Twelve patients met preset criteria for celiac crisis; 11 developed celiac crisis before they were diagnosed with celiac disease. Eleven patients had increased titres of transglutaminase antibodies and 1 had immunoglobulin A deficiency. Results of biopsy analyses of duodenum samples from all patients were consistent with a Marsh 3 score (33% with total villous atrophy). Patients presented with severe dehydration, renal dysfunction, and electrolyte disturbances. All patients required hospitalization and intravenous fluids, 6 required corticosteroids, and 5 required parenteral nutrition. All patients eventually had a full response to a gluten-free diet. CONCLUSIONS: Celiac crisis has a high morbidity and, although rarely described, occurs in adults and often has a clear precipitating factor. Patients who present with severe unexplained diarrhea and malabsorption should be tested for celiac disease; treatment with systemic steroids or oral budesonide should be considered. Nutritional support often is required in the short term but most patients ultimately respond to gluten avoidance.